Recent preliminary data suggests that CD4+ T cell homeostatic proliferation in T-deficient mice involves a cell cycle progression that opposes the development and maintenance of the T cell clonal anergy tolerance mechanism. Such resistance to clonal anergy induction in the lymphopenic immune system suggests an important relationship between T cell deficiency and an increased potential for the maintenance of clonal anergy in vivo, and investigate the relationship between homeostatic proliferation and clonal anergy. Specifically, three scientific aims will be addressed: 1) investigate Ag recognition in athymic nu/nu mutant mice, and test whether or not homeostatic proliferation in the T-deficient immune system leads to an avoidance of clonal anergy induction, 2) determine whether T-deficient mice are resistant to clonal anergy because of an increased co-stimulatory activity of their APC, and 3) examine anergic T cell clonal expansion in nu/nu mice, and determine how homeostatic proliferation leads to the reversal of clonal anergy. Results of this study will lead to a better understanding of the nature of clonal anergy induction and its reversal in both the normal and immunodeficient immune system. Furthermore, the study will provide important insight into the potential for autoimmunity as a consequence of T cell deficiency.